Trans-1(6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazine

ABSTRACT

A compound 4-((1R,3S)-6-Chloro-3-phenylindan-1-yl)-2,2-dimethylpiperazine and salts thereof, pharmaceutical compositions comprising the compound and salts, and medical use thereof, including for treatment of schizophrenia and other psychotic disorders.

This application is a §371 national stage of PCT InternationalApplication No. PCT/DK2004/000546, filed Aug. 18, 2004 on behalf of H.Lundbeck A/S, which is a continuation-in-part of and claims priority ofDanish Application No. PA 200301180, filed Aug. 18, 2003 and DanishApplication No. PA 200301305, filed Sep. 11, 2003, and claims benefit ofU.S. Provisional Application No. 60/496,058 filed Aug. 18, 2003 and U.S.Provisional Application No. 60/520,246 filed Nov. 14, 2003, the contentsof all of which are hereby incorporated by reference into the subjectapplication.

The present invention relates totrans-1-(6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazine and saltsthereof, in particular for medical use, including for treatment ofschizophrenia or other diseases involving psychotic symptoms.

BACKGROUND OF THE INVENTION

The compound, which is the subject of the present invention (Compound I,trans-1-((1R,3S)-6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazine)has the general formula (1).

A group of compounds structurally related to Compound I, i.e. transisomers of 3-aryl-1-(1-piperazinyl)indanes substituted in the 2- and/or3-position of the piperazine ring, has been described in EP 638 073;Bøgesø et al. in J. Med. Chem., 1995, 38, 4380-4392 and Klaus P. Bøgesøin “Drug Hunting, the Medicinal Chemistry of 1-Piperazino-3-phenylindansand Related Compounds”, 1998, ISBN 87-88085-10-4I. These compounds aredescribed as having high affinity for dopamine (DA) D₁ and D₂ receptorsand the 5-HT₂ receptor and are suggested to be useful for treatment ofseveral diseases in the central nervous system, including schizophrenia.

An enantiomer corresponding to the compound of the formula (I) butdiffering in that it has a methyl group instead of a hydrogen on thepiperazine has been disclosed in Bøgesø et al. in J. Med. Chem., 1995,38, 4380-4392, see table 5, compound (−)-38. This publication concludesthat the (−)-enantiomers of compound 38 is a potent D₁/D₂ antagonistsshowing some D₁ selectivity in vitro while in vivo it is equipotent asD₁ and D₂ antagonist. The compound is described as a potent 5-H T₂antagonist, having high affinity for α₁ adrenoceptors.

None of the above references disclose the specific enantiomeric formabove (Compound I) or the medical use thereof. The trans isomer in theform of the racemate of Compound 1 is only indirectly disclosed as anintermediate in the synthesis of compound 38 in Bøgesø et al. in J. Med.Chem., 1995, 38, 4380-4392) while the medical use of Compound I or ofits corresponding racemate is not described.

The aetiology of schizophrenia is not known, but the dopamine hypothesisof schizophrenia (Carlsson, Am. J. Psychiatry 1978, 135, 164-173),formulated in the early 1960s, has provided a theoretical framework forunderstanding the biological mechanisms underlying this disorder. In itssimplest form, the dopamine hypothesis states that schizophrenia isassociated with a hyperdopaminergic state, a notion which is supportedby the fact that all antipsychotic drugs on the market today exert somedopamine D₂ receptor antagonism (Seeman Science and Medicine 1995, 2,28-37). However, whereas it is generally accepted that antagonism ofdopamine D₂ receptors in the limbic regions of the brain plays a keyrole in the treatment of positive symptoms of schizophrenia, theblockade of D₂ receptors in striatal regions of the brain causesextrapyramidal symptoms (EPS). As described in EP 638 073 a profile ofmixed dopamine D₁/D₂ receptor inhibition has been observed with someso-called “atypical” antipsychotic compounds, in particular withclozapine, used in treatment of schizophrenic patients. Central alantagonistic actions has also been suggested to contribute in improvingantipsychotic properties (Millan et al, JPET, 2000, 292, 38-53).

Further, selective D₁ antagonists have been connected to treatment ofsleep disorders and alcohol abuse (D. N. Eder, Current Opinion inInvestigational Drugs, 2002 3(2):284-288). Dopamine may also play animportant role in the etiology of affective disorders (P. Willner,Brain. Res. Rev. 1983, 6, 211-224, 225-236 and 237-246; J. Med. Chem.1985, 28, 1817-1828).

In EP 638 073 is described how compounds having affinity for 5-HT₂receptors, in particular 5-HT₂ receptors antagonists, have beensuggested for treatment of different diseases, such as schizophreniaincluding the negative symptoms in schizophrenic patients, depression,anxiety, sleep disturbance, migraine attacks and neuroleptic-inducedparkinsonism. 5-HT₂ receptor antagonism has also been suggested toreduce the incidence of extrapyramidal side effects induced by classicalneuroleptics (Balsara et al. Psychopharmacology 1979, 62, 67-69).

DETAILED DESCRIPTION OF THE INVENTION

The Products of the Invention and the Medical use Thereof

The inventors have found that Compound I displays high affinity fordopamine D1 receptors, dopamine D2 receptors and for alfa1adrenoceptors. Furthermore, compound I has been found to be anantagonist at dopamine D1 and D2 receptors, and at serotonin 5-HT2areceptors. The pharmacological activities of compound I are with respectto these receptors found to be similar to that of the compound describedabove differing structurally from Compound I in that it has a methylgroup instead of a hydrogen on the piperazine.

The inventors have also found that several of the structurally relatedcompounds, both racemates and enantiomers, described in the abovementioned references are CYP2D6 (Cytochrome P450 2D6) inhibitors whereasCompound I is a relatively weak inhibitor of CYP2D6, also in comparisonwith other antipsychotics such as Haloperidole and Risperidone. Theracemate of the compound of the present invention is also considerablemore potent on the CYP2D6 enzyme compared to the enantiomer of thepresent invention, i.e. Compound I.

The CYP2D6 enzyme is a liver enzyme important for metabolism. CYP2D6 isa mammalian enzyme commonly associated with the metabolism ofpharmaceutical compounds and inhibition of this drug metabolizing enzymemay lead to clinically significant drug-drug interactions i.e. if twodrugs are given in combination and are metabolised by the same enzymes,competition for metabolism may give rise to increased plasmaconcentrations and therefore possible adverse effects (for review seeLin et al, Pharmacological Rev. 1997, 49, 403-449, Bertz R J andGranneman G R. Clin Pharmacokinet 1997, 32,210-258).

Since more than 80 drugs in clinical use (and in particular psychotropicdrugs) are metabolized by CYP2D6 (Bertz R J, Granneman G R. ClinPharmacokin 1997, 32, 210-58, Rendic S, DiCarlo F J. Drug Metab Rev1997, 29, 413-580), inhibition of this enzyme by coadministered drugscan lead to dramatic increases in exposure levels and resulting toxicityas seen with the combination of the well known CYP2D6 inhibitorsfluoxetine or paroxetine in combination with Imipramine, Desimipramineor Nortriptyline, resulting in increased cadiac toxicity of thesetricyclics (Ereshefsky L. el al. J. Clin. Psychiatry 1996, 57(supp18),17-25, Shulman R W Can J Psychiatry, Vol 42, Supplement 1, 4S).

The fact that Compound I has a low interaction with the liver enzymeCYP2D6 means that it has a reduced potential for drug to druginteraction, i.e. there is possibly less drug to drug interaction when apatient is treated with the compound of the present invention togetherwith other drugs which are mainly metabolised by the CYP2D6 enzyme. Thisis a considerable advantage, in particular for patients withschizophrenia which are often treated with other medicaments to controltheir disease.

The inventors have also found that Compound I has a relatively lowprolonging effect on the QT-interval in the electrocardiogram (ECG) ofthe “alpha-chloraose anaesthetised rabbit”. Drug-induced QT-intervalprolongation in the electrocardiogram (ECG) and the appearance of fatalcardiac arrhythmias, torsade de pointes (TdP), has become recognised asa potential risk during treatment with a broad range of drugs includingrepolarisation-delaying antiarrhythmics [C. L. Raehl, A. K. Patel and M.LeRoy, Clin Pharm 4 (1985), 675-690], various antihistamines [R. L.Woosley, Annu Rev Pharmacol Toxicol 36 (1996), 233-252; Y. G. Yap and A.J. Camm, Clin Exp Allergy 29 Suppl 1 (1999), 15-24], antipsychotics [A.H. Glassman and J. T. Bigger, Am J Psychiatry 158 (2001), 1774-1782] andanti-microbial agents [B. Darpö, Eur Heart J 3 Suppl K (2001), K70-K80].The fact that Compound I has a relatively low effect on the rabbit QTinterval means that this compound has a reduced potential forintroducing drug-induced QT interval prolongation and appearance offatal cardiac arrhythmias, torsade de pointes (TdP), in humans comparedto several commercialised antipsychotics.

Thus, in one aspect, the invention relates to the compound of formula I(Compound I) and salts thereof. The salt of the invention, i.e. of thecompound of formula (I), may, e.g., be selected from a fumarate or amaleate salt of Compound I.

The properties of Compound I indicate that it will be particularlyuseful as a pharmaceutical. Accordingly, the present invention furtherrelates to a pharmaceutical composition of Compound I of the inventionor a salt thereof. The invention also relates to the medical use of suchcompounds, salts and compositions, such as for the treatment of adisease in the central nervous system, including psychosis, inparticular schizophrenia or other diseases involving psychotic symptoms,such as, e.g., Schizophrenia, Schizophreniform Disorder, SchizoaffectiveDisorder, Delusional Disorder, Brief Psychotic Disorder, SharedPsychotic Disorder as well other psychotic disorders or diseases thatpresent with psychotic symptoms, e.g. mania in bipolar disorder.

Additionally, the 5-HT₂ antagonistic activity of the compound of theinvention suggests that the compound or salt thereof may have arelatively low risk of extrapyramidal side effects.

The present invention also relates to use of Compound I of theinvention, or a salt thereof for treatment of a disease selected fromthe group consisting of anxiety disorders, affective disorders includingdepression, sleep disturbances, migraine, neuroleptic-inducedparkinsonism, cocaine abuse, nicotine abuse, alcohol abuse and otherabuse disorders.

In a preferred embodiment, the present invention relates to a method oftreating Schizophreniform Disorder, Schizoaffective Disorder, DelusionalDisorder, Brief Psychotic

Disorder, Shared Psychotic Disorder or mania in bipolar disorder,comprising administering a therapeutically effective amount of CompoundI of the invention or a salt thereof.

A further embodiment of the invention relates to a method of treatingpositive symptoms of 5 schizophrenia comprising administering atherapeutically effective amount of Compound I or a salt thereof.

Another embodiment of the invention relates to a method of treatingnegative symptoms of schizophrenia comprising administering atherapeutically effective amount of the Compound I or a salt thereof.

A further embodiment of the invention relates to a method of treatingdepressive symptoms of schizophrenia comprising administering atherapeutically effective amount of Compound I or a salt thereof.

A further aspect of the invention relates to a method of treating maniaand/or maintenance of bipolar disorder comprising administering atherapeutically effective amount of Compound I or a salt thereof.

A further aspect of the invention relates to a method of treatingneuroleptic-induced parkinsonism comprising administering atherapeutically effective amount of the Compound I or a salt thereof.

The invention further relates to a method of treating substance abuse,e.g. nicotine, alcohol or cocaine abuse, comprising administering atherapeutically effective amount of Compound I or a salt thereof.

In a broad aspect, the present invention relates totrans-1-(6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazine or a saltthereof for use as a medicament.

Accordingly, the present invention also relates to a method of treatinga disease selected from the group consisting of a disease involvingpsychotic symptoms, schizophrenia (e.g. one or more of positivessymptoms, negative symptoms and depressive symptoms of schizophrenia),Schizophreniform Disorder, Schizoaffective Disorder, DelusionalDisorder, Brief Psychotic Disorder, Shared Psychotic Disorder, and maniain bipolar disorder, anxiety disorders, affective disorders includingdepression, sleep disturbances, migraine, neuroleptic-inducedparkinsonism, and abuse disorders, e.g. cocaine abuse, nicotine abuse,or alcohol abuse, comprising administering a therapeutically effectiveamount of the compoundtrans-1-(6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazine or a saltthereof.

As used herein the term“trans-1-(6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazine”, i.e.without any specific indication of the enantiomer form (e.g. using (+)and (−), or using the R/S-convention, is meant to refer to anyenantiomeric form of this compound, i.e. either of the two enantiomersor to a mixture of the two, e.g. the racemic mixture). However, in thiscontext preferably the content of the enantiomer corresponding to thatof Compound I is at least 50%, i.e. at least as the racemic mixture, butpreferably Compound I is in enantiomeric excess.

In the present context for the pharmaceutical uses it is understood thatwhen specifying the enantiomer form as done in formula (I) for CompoundI, then the compound is relatively stereochemically pure, preferably theenantiomeric excess is of at least 70%, and more preferably at least 80%(80% enantiomeric excess means that the ratio of I to its enantiomer is90:10 in the mixture in question) at least 90%, at least 96%, orpreferably at least 98%. In a preferred embodiment, the diastereomericexcess of Compound I is at least 90% (90% diastereomeric purity meansthe ratio of Compound I tocis-1-((1S,3S)-6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazine is95:5), at least 95%, at least 97%, or at least 98%.

A further aspect of the invention relates to a method of treatment asdescribed herein, wherein the patient treated with Compound I or a saltthereof is also treated with at least one other medicament. A particularrelevant embodiment in this connection, is treatment with othermedicaments being metabolised by CYP2D6.

In a suitable embodiment, the other medicament is an antipsychotic.Accordingly, one embodiment relates to the use of a compound, salt orpharmaceutical composition of the invention for treating a patientsuffering from schizophrenia or other psychoses who is also treated withother medicament(s), e.g. where this other medicament is anantipsychotic.

In another embodiment, the invention relates to the use of a compound ora salt of the invention for treating a patient suffering fromschizophrenia or other psychoses who is a substance abuser, e.g. ofalcohol or narcotics.

The compound, salt or composition of the invention may be administeredin any suitable way e.g. orally, buccal, sublingual or parenterally, andthe compound or salt may be presented in any suitable form for suchadministration, e.g. in the form of tablets, capsules, powders, syrupsor solutions or dispersions for injection. In one embodiment, thecompound or salt of the invention are administered in the form of asolid pharmaceutical entity, suitably as a tablet or a capsule.

Methods for the preparation of solid pharmaceutical preparations arewell known in the art. Tablets may thus be prepared by mixing the activeingredient with ordinary adjuvants, fillers and diluents andsubsequently compressing the mixture in a convenient tabletting machine.Examples of adjuvants, fillers and diluents comprise corn starch,lactose, talcum, magnesium stearate, gelatine, lactose, gums, and thelike. Any other adjuvant or additive such as colourings, aroma,preservatives, etc. may also be used provided that they are compatiblewith the active ingredients.

Solutions for injections may be prepared by dissolving a salt of theinvention and possible additives in a part of the solvent for injection,preferably sterile water, adjusting the solution to desired volume,sterilisation of the solution and filling in suitable ampules or vials.Any suitable additive conventionally used in the art may be added, suchas tonicity agents, preservatives, antioxidants, solubilising agentsetc.

The daily dose of the compound of formula (I) above, calculated as thefree base, is suitably between 1.0 and 160 mg/day, more suitable between1 and 100 mg, e.g. preferably between 2 and 55 mg.

The term “treatment” as used herein in connection with a disease ordisorders includes also prevention as the case may be.

Method of Preparation

The compound of formula (I) in racemic form may, e.g., be preparedanalogously to the methods outlined in EP 638 073, and in Bøgesø et al.J. Med. Chem., 1995, 38, page 4380-4392 followed by optical resolutionof the racemic compound by crystallisation of diastereomeric saltsthereby obtaining the enantiomer of formula (I).

The present inventors have developed a route of synthesis in which theenantiomer of formula (I) is obtained via a synthetic sequence startingfrom enantiomeric pure V, i.e. compound Va((1S,3S)-6-chloro-3-phenylindan-1-ol, see below). Thus, in this process,the intermediate of formula V is resolved, e.g. by chiral chromatographyor enzymatically, to obtain the enantiomer of formula Va. This new routeof synthesis to obtain the compound of formula (I) is more efficientthan the above mentioned crystallisation of diastereomeric salts of thefinal product I, e.g. the resolution of an intermediate instead of thefinal product gives a much more efficient synthesis, as only the wantedenantiomer is used in the subsequent steps, giving e.g. higher volumeyields and less consumption of reagents.

Accordingly, the enantiomer of formula (I) may be obtained by a processinvolving the following steps:

Benzyl cyanide is reacted with 2,5-dichlorobenzonitril in the presenceof a base, suitably potassium tert-butoxide (t-BuOK) in a suitablesolvent such as dimethyl ether (DME), further reaction with methylchloro acetate (MCA) leads to spontaneous ring closure and one potformation of the compound of formula (I).

The compound of formula (II) is then subjected to acidic hydrolysis toform a compound of formula (III), suitably by heating in a mixture ofacetic acid, sulphuric acid and water, and thereafter decarboxylation byheating the compound of formula (III) in a suitable solvent, such astoluene with triethyl amine or N-methyl pyrrolidin-2-one (NMP), to forma compound of formula (IV).

The compound of formula (IV) is then reduced, suitably with sodiumborohydride (NaBH₄) in a solvent such as an alcohol, e.g. ethanol oriso-propanol, and preferably at a temperature in the range of −30° to+30° C., e.g. below 30° C., below 20° C., below 10° C., or preferablybelow 5° C., to form a compound of formula (V) with cis configuration:

The compound of formula (V) is resolved to achieve the desiredenantiomer (formula Va), i.e. also with cis configuration((1S,3S)-6-chloro-3-phenylindan-1-ol):

The resolution of (V) to (Va) may, e.g., be performed using chiralchromatography, preferably liquid chromatography, suitably on a chiralcolumn of silicagel coated with a chiral polymer, e.g. a modifiedamylose, preferably amylose tris-(3,5-dimethylphenylcarbamate) coated onsilicagel. A suitable solvent is used for the chiral liquidchromatography, such as, e.g. an alcohol, a nitrile, an ether, or analkane, or mixtures thereof, suitably ethanol, methanol, iso-propanol,acetonitrile, or methyl tert-butyl ether or mixtures thereof, preferablymethanol or acetonitrile. The chiral liquid chromatography can be scaledup using suitable technologies, e.g. simulated moving bed technology(SMB).

Alternatively, the compound of formula (V) is resolved to achieveCompound Va by enzymatic resolution. It has been found thatenantiomerically pure Compound Va, or acylated derivatives thereof, maybe prepared by enzymatic enantioselective acylation of the hydroxylgroup in racemic Compound V to obtain Compound Va or an acylatedderivative thereof with high optical purity. Alternatively,enantiomerically pure Compound Va may also be obtained by a processcomprising converting racemic Compound V to the corresponding esterderivative,. i.e. an ester group at the hydroxyl position followed by anenzymatic enantioselective deacylation. Use of enzymaticenantioselective deacylation has been reported for other compounds.

Accordingly, the resolution of Compound V to Compound Va may beperformed by selective enzymatic acylation. Selective enzymaticacylation means that the enzymatic acylation is preferentially effectivefor conversion of one of the cis-enantiomers of the compound of formulaV to the corresponding acetylated derivative Vb leaving the othercis-enantiomer of Compound V, e.g. compound Va, as unconverted in thereaction mixture as outlined in the following:

wherein R, e.g., is acetate, propionate, butyrate, valerate, hexanoate,benzoate, laurate, isobutyrate, 2-methylbutyrate, 3-methylbutyrate,pivalate, 2-methylvalerate, 3-methylvalerate, or 4-methylvalerate.Suitable irreversible acyldonors are, e.g, vinyl-esters,2-propenyl-esters or 2,2,2-trihalid-ethyl-esters. Alternatively, theother enantiomer is acetylated (i.e. acetylated Va is the product, notshown), and the alcohol Va can subsequently be obtained by isolation ofacetylated Va and subsequent removal of the ester group.

Alternatively, The resolution of Compound V to Compound Va may beperformed by selective enzymatic deacylation. Selective enzymaticdeacylation means that the enzymatic deacylation is preferentiallyeffective for conversion of one of the esters of compound of formula V(Vc), leaving the other cis-enantiomer of esters of a compound offormula V (Vd) as unconverted in the reaction mixture.

Suitable esters (Vc) of the compound of formula (V) are esters such asacetate, propionate, butyrate, valerate, hexanoate, benzoate, laurate,isobutyrate, 2-methylbutyrate, 3-methylbutyrate, pivalate,2-methylvalerate, 3-methylvalerate, 4-methylvalerate,

wherein R¹, e.g., is acetate, propionate, butyrate, valerate, hexanoate,benzoate, laurate, isobutyrate, 2-methylbutyrate, 3-methylbutyrate,pivalate, 2-methylvalerate, 3-methylvalerate, or 4-methylvalerate.Alternatively the ester of Va is left unconverted in the reactionmixture (i.e. acetylated Va is the product, not shown) and the alcoholVa can subsequently be obtained by isolation of acetylated Va andsubsequent removal of the ester group by standard procedures.

Thus, enantioselective enzymatic acylation means that the enzymaticacylation is preferentially effective for conversion of one of theenantiomers of a compound of formula (V) preferentially leaving theother enantiomer of the compound of formula (V) unconverted in thereaction mixture. Enantioselective enzymatic deacylation means that theenzymatic deacylation is preferentially effective for conversion of oneof the enantiomers of a compound of formula (Vc), preferentially leavingthe other enantiomer of the compound of formula (Vc) unconverted in thereaction mixture.

Thus, one embodiment relates to a process for the preparation of the (S,S)— or (R, R)-enantiomer of the compound of formula V (i.e. with cisconfiguration) comprising:

a) subjecting a racemic Compound V to enantioselective enzymaticacylation using an acylating agent, or

b) subjecting a racemic Compound Vc to entantioselective enzymaticdeacylation to form a mixture of deacylated Compound Va.

The mixtures obtained by the enzymatic resolution may not be entirelypure, e.g. they may contain a smaller amount of the other enantiomer inaddition to a larger amount of the desired enantiomer (Va). Thecomposition mixture obtained after acylation or deacylation according tothe invention depend, e.g., on the specific hydrolase used and theconditions under which the reaction is carried out. Characteristic ofthe enzymatic acylation/deacylation according to the invention is that aconsiderably larger portion of one enantiomer is converted than of theother. The enantioselective acylation according to the invention thusresults in a mixture containing preferentially the compound of formula(Vb) in the (R,R)-form and the compound of formula (Va) in the(S,S)-form, or it may result in a mixture containing preferentially thecompound of formula (Vb) in the (S,S)-form and the compound of formula(Va) in the (R,R)-form. Likewise, the enantioselective enzymaticdeacylation may result in a mixture containing preferentially thecompound of formula (Vd) in the (S,S)-form and the compound of formula(Va) in the (R,R)-form, or it may result in a mixture containingpreferentially the compound of formula (Vd) in the (R,R)-form and thecompound of formula (Va) in the (S,S)-form. The optical purity of the Vaobtained by the optical resolution method of the present invention isusually at least 90% ee., preferably at least 95% ee., more preferablyat least 97% ee and most preferably at least 98% ee. However, lowervalues for the optical purity are acceptable.

According to the invention, enantioselective enzymatic acylation iscarried out under conditions substantially suppressing hydrolysis.Hydrolysis, which is the reverse reaction of the acylation reaction,takes place if water is present in the reaction system. Thus,enantioselective enzymatic acylation is preferably carried out in awater-free organic solvent or almost anhydrous organic solvent ( enzymesnormally require the presence of some water to be active). Suitablesolvents include hydrocarbons such as hexane, heptane, benzene andtoluene; ethers such as diethyl ether, diisopropyl ether,tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether anddimethoxyethane; ketones such as acetone, diethyl ketone, butanon, andmethyl ethyl ketone; esters such as methyl acetate, ethyl acetate, ethylbutyrate, vinyl butyrate and ethyl benzoate; halogenated hydrocarbonssuch as methylene chloride, chloroform and 1,1,1-trichloroethane;secondary and tertiary alcohols, such as tert-butanol;nitrogen-containing solvents such as dimethylformamide, acetoamide,formamide, acetonitrile and propionitrile; and aprotic polar solventssuch as dimethylsulfoxide, N-methylpyrrolidin-2-one andhexamethylphosphorous triamide. Preferred organic solvents for enzymaticacylation are organic solvents such as toluene, hexane, heptane, dioxaneand tetrahydrofuran (THF).

Suitable irreversible acyldonors are, e.g., acyldonors such asvinyl-esters, 2-propenyl-esters or 2,2,2-trihalid-ethyl-esters.

Enantioselective enzymatic deacylation is preferably carried out inwater or a mixture of water and an organic solvent, suitable in presenceof a buffer. Suitable organic solvents, e.g., are solvents miscible withwater such as alcohols, acetonitrile, dimethyl formamide (DMF), dimethylsulfoxide (DMSO), 1,4-dioxane, DME and diglyme.

It has been found that enzymatic acylation according to the inventionmay be carried out using Novozym 435 (Candida Antarctica lipase B, fromNovozymes A/S, Fluka Cat.-No. 73940). In general, the enzymaticacylation or deacylation according to the invention is preferablycarried out using a lipase, an esterase, an acylase or a protease. Theenzymes useful according to the invention are such enzymes capable ofperforming R-selective acylation or S-selective acylation of the hydroxygroup in the racemic compound of formula (V) or such enzymes which arecapable of performing R-selective deacylation or S-selective deacylationof the acyl group in the racemic compound of formula (Vc). In particularimmobilized forms of the enzyme, including Cross-Linked Enzyme Crystal(CLEC) are useful according to the invention. A preferred embodimentrelates to use of a lipase for carrying out the enzymatic resolution ofCompound V. The most preferred lipase is Candida antarctica lipase(Fluka Cat.-No. 62299); Pseudomonas cepacia lipase (Fluka Cat.-No.62309); Novozym CALB L (Candida antarctica lipase B) (Novozymes A/S);Novozym 435 (Candida antarctica lipase B) (Novozymes A/S); or LipozymeTL IM (Thermomyces lanuginosus lipase) (Novozymes A/S), preferably inimmobilized form.

The alcohol group of the cis-alcohol of formula (Va) is converted to asuitable leaving group, such as, e.g., a halogen, e.g. Cl or Br,preferably Cl, or a sulphonate, e.g. mesylate or tosylate, suitably byreaction with an agent, such as thionyl chloride, mesyl chloride ortosyl chloride, in an inert solvent, e.g. an ether, suitablytetrahydrofuran. The resulting compound has formula (VI), where LG isthe leaving group:

In a preferred embodiment, LO is Cl, i.e. the cis-chloride of formula(VIa):

Compound VI, e.g. with LG as chloro, is then reacted with2,2-dimethylpiperazine in a suitable solvent, e.g. a ketone such as,e.g., methyl isobutyl ketone or methyl ethyl ketone, preferably methylisobutyl ketone in presence of a base, such as e.g., potassiumcarbonate, to obtain Compound I.

Furthermore, the piperazine part of the molecule may be introduced byreacting Compound VI with a compound of formula (VII) below, where PG isa protecting group such as, but not restricted to, e.g.phenylmethoxycarbonyl (often called Cbz or Z), tert-butyloxycarbonyl(often called BOC), ethoxycarbonyl, or benzyl, thereby obtaining thecompound of formula (VIII) below. Compound VIII is subsequentlydeprotected to Compound I.

During the synthesis some cis diastereoisomer of Compound I (i.e.1-((1S,3S)-6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazine) isformed as an impurity in the final product. This impurity is due mainlyto the formation of some of the trans form of (VI) (e.g.(1S,3R)-3,5-dichloro-1-phenylindan when LG is Cl) in the step whereCompound VI is formed. Therefore, the impurity can be minimized bycrystallisation of the desired cis form of Compound VI, from the mixtureof trans and cis (VI); in the case where LG is Cl in Compound VI thiscan be done by stirring the mixture with a suitable solvent, e.g. analkane, such as heptane, whereby the desired cis form of VI precipitatesand the undesired trans form of Compound VI goes into solution. Thedesired cis form of Compound VI (e.g. when LG is Cl) is isolated byfiltration, washed with the solvent in question and dried.

The cis form of Compound I may also be removed by precipitation of asuitable salt of the compound of formula Compound I, e.g. a salt of anorganic acid, such as an organic diacid, suitably a fumarate salt or amaleate salt of the compound of formula (I), optionally followed by onemore re-crystallisations.

The invention in further aspects also relates to the intermediates asdescribed herein for the synthesis of the compound of formula (I), i.e.in particular the intermediates Va and VI, including Compound VIa. Inthis context is understood that when specifying the stereoisomeric form,then the stereoisomer is the main constituent of the compound. Inparticular, when specifying the enantiomeric form, then the compound hasan enantiomeric excess of the enantiomer in question.

Accordingly, one embodiment of the invention relates to the compound offormula (Va), preferably having an enantiomeric excess of at least 60%(60% enantiomeric excess means that the ratio of Va to its enantiomer is80:20 in the mixture in question), at least 70%, at least 80%, at least85%, at least 90%, at least 96%, preferably at least 98%. Furthermore,the diastereomeric excess of the compound is preferably at least 70%(70% diastereomeric excess means, that the ratio of Compound Va to(1R,3S)-6-chloro-3-phenylindan-1-ol is 85:15 in the mixture inquestion), at least 80%, at least 85%, at least 90%, or at least 95%.One embodiment relates to substantially pure Compound Va.

A further embodiment of the invention relates to the compound of formula(VI), preferably having an enantiomeric excess of at least 60%, at least70%, at least 80%, at least 85%, at least 90%, at least 96%, preferablyat least 98%,

wherein LG is a potential leaving group, preferably selected from thegroup consisting of a halogen, e.g. chloride, or a sulphonate. Oneembodiment relates to the diastereomeric purity of Compound VI; i.e. thecompound having a diasteromeric excess of preferably at least 10% (10%diastereomeric excess means that the ratio of Compound VI to the transdiastereoisomer (e.g. (1S,3R)-3,5-dichloro-1-phenylindan when LG=Cl) is55:45 in the mixture in question), at least 25% or at least 50%. Oneembodiment, relates to substantially pure Compound VI.

Accordingly, the invention also relates to a compound having thefollowing formula (VIa),

preferably having an enantiomeric excess of at least 60%, at least 70%,at least 80%, at least 85%, at least 90%, at least 96%, preferably atleast 98%. One embodiment relates to the diastereomeric purity of thecompound, i.e. the compound having a diastereomeric excess of,preferably at least 10% (10% diastereomeric excess means that the ratioof the compound to the trans diastereoisomer,(1S,3R)-3,5-dichloro-1-phenylindan, is 55:45 in the mixture inquestion), at least 25% or at least 50%. One embodiment relates tosubstantially pure Compound VI where LG is Cl.

As indicated above the invention in a particular interesting embodimentrelates to:

-   -   Compound I or a salt thereof,    -   a pharmaceutical compositions as described herein comprising        Compound I or a salt thereof,    -   a medical use as described herein for Compound I or a salt        thereof,

wherein Compound I is having an enantiomeric excess of at least 60% (60%enantiomeric excess means that the ratio of Compound I to its enantiomeris 80:20 in the mixture in question), at least 70%, at least 80%, atleast 85%, at least 90%, at least 96%, preferably at least 98%.

One embodiment relates to Compound I or a salt thereof and the uses asdescribed herein, wherein Compound I is having a diastereomeric excessof at least 10% (10% diastereomeric excess means that the ratio ofCompound I to the cis-(1S,3S) diastereoisomer is 55:45 in the mixture inquestion), at least 25%, at least 50%, at least 70%, at least 80%, atleast 90%, at least 95%, at least 97%, preferably at least 98%.

One embodiment relates to substantially pure Compound I or a saltthereof; also for a medical use as described herein.

A further aspect relates to Compound I or a salt thereof, in particularthe fumarate or maleate salt, obtainable, in particular obtained, by amethod of the invention as described herein; also for a medical use asdescribed herein.

The invention will be illustrated in the following non-limitingexamples.

EXAMPLES

Pharmacology

Binding Assays

For all assays: Results are expressed as percent inhibition of controlspecific binding and the IC₅₀ values (concentration causing ahalf-maximal inhibition of control specific binding) are determined bynon-linear regression analysis using Hill equation curve fitting. Theinhibition constants (K_(i)) were calculated from the Cheng Prusoffequation K_(i)=IC₅₀/(1+(L/K_(D))), where L equals the concentration ofradioligand in the assay) and K_(D) equals the affinity of theradioligand for the receptor.

Alpha-1 Adrenoceptors Subtyes

Chinese hamster ovary (CHO) cell lines expressing rat alpha_(1d) andBaby hamster Kidney (BHK) cells expressing bovine alpha_(1a) weregenerated using standard stable transfection techniques. The Rat-1 cellline expressing the hamster alpha_(1b) receptor was obtained fromUniversity of Utah, Salt Lake City, Utah. Cell lines expressing theappropriate (alpha_(1a), alpha_(1b), alpha_(1d)) receptors wereharvested and homogenized in ice-cold 50 mM Tris pH 7.7 using anUltra-Turrax homogenizer and either stored at −80° C. on kept on iceuntil used. [³H]Prazosin (0.3-0.5 nM) was used as radioligand assessingthe affinity of subtypes of alpha₁ receptors. Total binding wasdetermined using assay buffer and non-specific binding was defined inthe presence of 1 μM WB-4101 for all subtypes of alpha₁ receptors.Aliquots were incubated 20 min at 25° C. In all assays bound and freeradioactivity were separated by vacuum filtration on GF/B filterspretreated with Polyetyleneimine (PEI) and counted in a scintillationcounter.

Alpha-1 Adrenoceptors (Inhibition of Binding of [³H]Prazosine to RatAlpha-1-Receptors)

By this method, the inhibition by drugs of the binding of [³H]Prazosin(0.25 nM) to alpha-1 receptors in membranes from rat brain is determinedin vitro. Method modified from Hyttel et al. J. Neurochem. 1985, 44,1615-1622.

DA D1 Receptors:

Affinities towards human D1 receptors were determined at the contractlaboratory Cerep using the catalog reference assay no 803-1h. Membranesfrom CHO cells expressing human recombinant D1 receptors were used. 0.3nM [³H]-SCH23390 was used as radioligand and compounds were tested in aserial dilution concurrently with the reference compound SCH23390 inorder to assess the assay suitability. Aliqouts were incubates at 22° C.for 60 min and bound radioactivity are measured with a liquidscintillation counter.

Specific control binding to the D1 receptors was defined as thedifference between the total binding determined without compound presentand the non-specific binding determined in the presence of 1 μm SCH23390.

DA D2 Receptors:

CHO cells expressing approximately 800 fmol/mg human recombinant D2receptors were generated standard stable transfection techniques.Membranes were harvested using standard protocols and affinities weremeasured by the addition of a serial dilution of compound to a membranepreparation in a mixture of 50 mM Tris-HCl, 120 mM NaCl, 4 mM MgCl_(2.)0.1 nM ³[H]-Spiperone was used as the radioligand assessing the affinityfor the human D2 receptor. Total binding was determined in the presenceof buffer and non-specific binding was determined in the presence of 10μM haloperidol. The mixture was incubated for 30 minutes at 37° C.,cooled briefly on ice. Bound and free radioactivity was separated byvacuum filtration on GF/C filters pretreated with 0.1% Polyetyleneime(PEI) and filters were counted in a scintillation counter.

Efficacy Assays

DA D1 Receptors:

The ability of the compounds to inhibit the D1 receptor mediated cAMPformation in a CHO cell line generated in-house stably expressing thehuman recombinant D1 receptor was measured as follows. Cells were seededin 96-well plates at a concentration of 11000 cells/well 3 days prior tothe experiment. On the day of the experiment the cells were washed oncein preheated G buffer (1 mM MgCl₂, 0.9 mM CaCl₂, 1 mM IBMX in PBS) andthe assay was initiated by addition of 100 μl of a mixture of 30 nMA68930 and test compound diluted in G buffer. The cells were incubatedfor 20 minutes at 37° C. and the reaction was stopped by the addition of100 μl S buffer (0.1 M HCl and 0.1 mM CaCl₂) and the plates were placedat 4° C. for 1 hour. 68 μl N buffer (0.15 M NaOH and 60 mM NaAc) wasadded and the plates were shaken for 10 minutes. 60 μl of the reactionwere transferred to cAMP FlashPlates (DuPont NEN) containing 40 μl 60 mMNaAc pH 6.2 and 100 μl IC mix (50 mM NaAc pH 6.2, 0.1% NaAzid, 12 mMCaCl₂, 1% BSA and 0.15 μCi/ml ¹²⁵I-cAMP) were added. Following an18-hour incubation at 4° C. the plates were washed once and counted in aWallac TrLux counter.

DA D2 Receptors:

The ability of the compounds to inhibit the D2 receptor mediatedinhibition of cAMP formation in CHO cells transfected with the human D2receptor was measure as follows.

Cells were seeded in 96 well plates at a concentration of 8000cells/well 3 days prior to the experiment. On the day of the experimentthe cells were washed once in preheated G buffer (1 mM MgCl₂, 0.9 mMCaCl₂, 1 mM IBMX in PBS) and the assay was initiated by addition of 100μl of a mixture of 1 μM quinpirole, 10 μM forskolin and test compound inG buffer. The cells were incubated 20 minutes at 37° C. and the reactionwas stopped by the addition of 100 μl S buffer (0.1 M HCl and 0.1 mMCaCl₂) and the plates were placed at 4° C. for 1 hour. 68 μl N buffer(0.15 M NaOH and 60 mM NaAc) were added and the plates were shaken for10 minutes. 60 μl of the reaction were transferred to cAMP FlashPlates(DuPont NEN) containing 40 μl 60 mM NaAc pH 6.2 and 100 μl IC mix (50 mMNaAc pH 6.2, 0.1% NaAzid, 12 mM CaCl₂, 1% BSA and 0.15 μCi/ml ¹²⁵I-cAMP)were added. Following an 18-hour incubation at 4° C. the plates werewashed once and counted in a Wallac TriLux counter.

Serotonin 5-HT2A Receptors

2 or 3 days before the experiment, CHO cells expressing 250 fmol/mgS-HT_(2A) receptors are plated at a density sufficient to yield amono-confluent layer on the day of the experiment. The cells are dyeloaded (Ca²⁺-kit from Molecular Devices and using Hank's balanced saltw/o phenol red, added 20 mM HEPES and pH adjusted to 7.4 with 2M NaOH asassaybuffer) for 60 minutes at 37° C. in a 5% CO₂ incubator at 95%humidity. Lacer intensity is set to a suitable level to obtain basalvalues of approximately 8000-10000 fluorescence units. The variation inbasal fluorescence should be less than 10%. EC₅₀ values are assessedusing increasing concentrations of test compound covering at least 3decades. IC₅₀ values are assessed challenging the same range ofconcentrations of test substances with EC₈₅ of 5-HT. Test substances areadded to the cells 5 minutes before the 5-HT. K_(i) values werecalculated using Cheng-Prusoff equation. % Stimulation of aconcentration of the test compound is measured with respect to a maximalconcentration of 5-HT (100%). % Inhibition of a concentration of thetest compound is measured as the percentage with which the response ofEC₈₅ of 5-HT is lowered. Maximum inhibition is the level of inhibitionthe curve reaches. It is expressed as the percentage inhibition at thatlevel and used to distinguish full and partial antagonists.

In Vitro Determination of the Interaction of Compounds with CYP2D6(CYP2D6 Inhibitor Assay

Principle: The inhibition of human CYP2D6 is assessed using microsomesprepared from baculovirus/insect cells cDNA expressing CYP2D6 as enzymesources and the specific CYP2D6 substrate AMMC(3-[2-(N,N-diethyl-N-methylammonium)-ethyl]-7-methoxy-4-methylcoumarin).AMMC is O-demethylated to AHMC(3-[2-(N,N-diethylamino)ethyl]-7-hydroxy-4-methylcoumarin) which isdetected by measuring appearance of fluorescence. Preferred compounds ofthe present invention exhibit an IC50 higher than 5 micromolar forCYP2D6 activity, the IC50 being the concentration of the compound thatgives 50% of inhibition of the CYP2D6 activity.

Material and Methods:

Microsomes prepared from baculovirus/insect cells cDNA expressing CYP2D6were obtained from BD Biosciences (Gentest 456217). Fluorescencemeasured Ex. (405 nm) Em. (465 nm) by a SpectroFluor Plus Plate Reader(Tecan Nordic). Incubations with the recombinant CYP2D6 micrsomescontained 1.5 pmol of the recombinant CYP2D6 in 0.2 ml total volume 100mM phosphate buffer at pH 7.4 containing 1.5 AMMC(3-[2-(N,N-diethyl-N-methylammonium)-ethyl]-7-methoxy-4-methylcoumarin)with a low NADPH-regenerating system consisting of 0.0082 mM NADP⁺, 0.41mM glucose 6-phosphate, 0.41 mM magnesium chloride and 0.4 units/mlglucose-6-phoshate dehydrogenase. The incubation time was 45 min and theincubations were quenched by addition of 0.075 ml 80% Acetonitrile 20%0.5 M Tris base. All chemicals were of analytical grade from Sigma (St.Louis, Mo.). IC50 curves were produced using 8 concentration between 40and 0.02 micromolar of the compounds to be tested dissolved in DMSO(dimethyl sulfoxide)—final conc. in incubations were below 1.0%(Modified from N. Chauret et. al. DMD Vol. 29, Issue 9, 1196-1200,2001). The IC₅₀ values were calculated by linear interpolation.

QT-Interval

Anaesthetised Rabbit:

The model described in the following was originally designed as aproarrhytmic model by Carlsson et al, [J Cardiovasc Pharmacol.1990;16:276-85.] and has been modified to fit into screening set-up asdescribed below under “animal preparation”.

Animal Preparation

Male rabbits (HsdIf:NZW, outbreed) weighing 2.0-2.8 kg were purchasedfrom Harlan (The Netherlands). Individual body weights were measured andrecorded on the day of experiment. General anaesthesia was induced viathe marginal ear vein by an intravenous infusion of pentobarbital (10mg/ml, 18 mg/kg) followed by (alpha-chloralose (100 mg/kg, infusionvolume 4 ml/kg administered over a 20 min period). The trachea wascannulated and the rabbits were ventilated with air at 45 strokes permin and a tidal volume of 6 ml/kg. A vascular catheter was implanted inthe jugular vein for test compound administration. Additional catheterswere implanted in the left carotid artery for blood sampling and bloodpressure monitoring. Needle electrodes were placed subcutaneously torecord the standard bipolar lead II: the negative electrode was placedin front of the right shoulder, the positive electrode close to the leftloin.

Experimental Protocol

Following a short period of equilibration, pre-dose values were obtainedat −20, −10 and 0 min prior to an IV bolus administration of vehicle ortest compound. The effect of the bolus administration was followed for a40 min period.

Data Sampling and Calculating

ECG, blood pressure and HR were continuously recorded on a Maclab 8/susing the Chart software v3.6.1 for the Macintosh computer. The samplingfrequency was 1000 Hz. Effects on the electrocardiogram (PQ-, QRS-, QT-,QTc-intervals and heart rate) and mean arterial blood pressure (MAP)were recorded and measured electronically.

Analytical Methods

The enantiomeric excess of compound (Va) in Example 1a is determined bychiral HPLC using a CHIRALCEL® OD column, 0.46 cm ID×25 cm L, 10 μm at40° C. n-Hexan/ethanol 95:5 (vol/vol) is used as mobile phase at a flowrate of 1.0 ml/min, detection is performed using a UV detector at 220nm.

HPLC Analysis for Conversion Rate Used for Examples 1b:

Column: A Lichrospher RP-8 column, 250×4 mm (5 μm particle size)

Eluent: Buffered MeOH/water prepared as follows: 1.1 ml Et₃N added to150 ml water, 10% H₃PO₄(aq) is added to pH=7 and water is added to atotal of 200 ml. The mixture is added to 1.8 L MeOH.

The enantiomeric excess of compound (Va) in example 1b is determined bychiral HPLC using a CHIRALPAK® AD column, 0.46 cm D×25 cm L, 10 μm at21° C. Heptane/ethanol/Diethylamine 89.9:10:0.1 (vol/vol/vol) is used asmobile phase at a flow rate of 1.0 ml/min, detection is performed usinga UV detector at 220 nm.

The enantiomeric excess of compound (I) is determined by fused silicacapillary electrophoresis (CE) using the following conditions: Capillar:50 μm ID×48.5 cm L, run buffer: 1.25 mM β cyclo dextrin in 25 mM sodiumdihydrogen phosphate, pH 1.5, voltage: 16 kV, temperature: 22° C.,injection: 40 mbar for 4 seconds, detection: column diode arraydetection 195 nm, sample concentration: 500 μg/ml. In this system,Compound I has a retention time of approximately 10 min, and the otherenantiomer has a retention time of approximately 11 min.

¹H NMR spectra is recorded at 500.13 MHz on a Bruker Avance DRX500instrument or at 250.13 MHz on a Bruker AC 250 instrument. Chloroform(99.8% D) or dimethyl sulfoxide (99.8% D) is used as solvents, andtetramethylsilane (TMS) is used as internal reference standard.

The cis/trans ratio of compound I is determined using ¹H NMR asdescribed in Bøgesø et al., J. Med. Chem. 1995, 38,4380-4392 (page 4388,right column). The cis/trans ratio of compound VI is determined by ¹HNMR in chloroform, using the integrals of the signal at 5.3 ppm for thecis isomer and the signal at 5.5 ppm for the trans isomer. Generally, acontent of approximately 1% of the undesired isomer can be detected byNMR.

The Melting Points are measured using Differential Scanning Calorimetry(DSC). The equipment is a TA-Instruments DSC-2920 calibrated at 5°/minto give the melting point as onset value. About 2 mg of sample is heated5°/min in a loosely closed pan under nitrogen flow.

Synthesis

Synthesis of Key Starting Material

Compound V was synthesised from IV by reduction with sodium borohydride(NaBH₄) adapting a method described in Bøgesø J. Med. Chem. 1983, 26,935, using ethanol as solvent, and performing the reaction atapproximately 0° C. Both compounds are described in Bøgesø et al. J.Med. Chem. 1995, 38, 4380-4392. Compound IV was synthesised from IIusing the general procedures described in Sommer et al., J. Org. Chem.1990, 55, 4822, which also describes II and the synthesis thereof.

EXAMPLE 1a Synthesis of (1S,3S)-6-chloro-3-phenylindan-1-ol (Va) by useof Chiral Chromatography

Racemic cis-6-chloro-3-phenylindan-1-ol (V) (492 grams) is resolved bypreparative chromatography, using a CHIRALPAK® AD column, 10 cm ID×50 cmL, 10 μm at 40° C. Methanol is used as mobile phase at a flow rate of190 ml/min, detection is performed using a UV detector at 287 nm. Theracemic alcohol (V) is injected as a 50,000 ppm solution in methanol; 90ml is injected with intervals of 28 min. All the fractions, whichcontain the title compound with more than 98% enantiomeric excess, arecombined and evaporated to dryness using a rotary evaporator, followedby drying “in vacuo” at 40° C. Yield 220 grams as a solid. Elementalanalysis and NMR conform to the structure, the enantiomeric excess ishigher than 98% according to chiral HPLC, [α]_(D) ²⁰+44.5° (c=1.0,methanol).

EXAMPLE 1b Synthesis of (1S,3S)-6-chloro-3-phenylindan-1-ol (Va) by useof Enzymatic Resolution

Compound V (5 g, 20.4 mmol) is dissolved in 150 ml anhydrous toluene.0.5 g Novozym 435 (Candida Antarctica lipase B) (Novozymes A/S, FlukaCat.-No. 73940) is added followed by vinylbutyrate (13 ml, 102.2 mmol).The mixture is stirred using mechanical stirrer at 21° C. After 1 day,an additional 0.5 g Novozym 435 is added. After 4 days at a conversionof 54%, the mixture is filtered and concentrated in vacuo to obtain anoil containing a mixture of (1R,3R)-cis-6-chloro-3-phenylindan-1-ol-butyrate ester and desired compoundVa with an enantiomeric excess of 99.2% (99.6% compound Va and 0.4% (1R,3R)-cis-6-chloro-3-phenylindan-1-ol).

EXAMPLE 2 Synthesis of (1S,3S)-3,5-dichloro-1-phenylindan (VI, LG=CI)

Cis-(1S,3S)-6-chloro-3-phenylindan-1-ol (Va) (204 grams) obtained asdescribed in Example 1a is dissolved in THF (1500 ml) and cooled to −5°C. Thionyl chloride (119 grams) is added dropwise as a solution in THF(500 ml) over a period of 1 h. The mixture is stirred at roomtemperature over night. Ice (100 g) is added to the reaction mixture.When the ice has melted the water phase (A) and the organic phase (B)are separated, and the organic phase B is washed twice with saturatedsodium bicarbonate (200 ml). The sodium bicarbonate phases are combinedwith water phase A, adjusted to pH 9 with sodium hydroxide (28%), andused to wash the organic phase B once again. The resulting water phase(C) and the organic phase B are separated, and the water phase C isextracted with ethyl acetate. The ethyl acetate phase is combined withthe organic phase B, dried with magnesium sulphate, and evaporated todryness using a rotary evaporator, giving the title compound as an oil.Yield 240 grams, which is used directly in the example 5. Cis/transratio 77:23 according to NMR.

EXAMPLE 3 Synthesis of 3,3-dimethylpiperazin-2-one

Potassium carbonate (390 grams) and ethylene diamine (1001 grams) arestirred with toluene (1.50 l). A solution of ethyl 2-bromoisobutyrate(500 grams) in toluene (750 ml) is added. The suspension is heated toreflux over night, and filtered. The filter cake is washed with toluene(500 ml). The combined filtrates (volume 4.0 l) are heated on a waterbath and distilled at 0.3 atm. using a Claisen apparatus; first 1200 mldistillate is collected at 35° C. (the temperature in the mixture is 75°C.). More toluene is added (600 ml), and another 1200 ml distillate iscollected at 76° C. (the temperature in the mixture is 80° C.). Toluene(750 ml) is added again, and 1100 ml of distillate is collected at 66°C. (temperature in the mixture 71° C.). The mixture is stirred on an icebath and inoculated, whereby the product precipitates. The product isisolated by filtration, washed with toluene, and dried over night in avacuum oven at 50° C. Yield 171 g (52%) of 3,3-dimethylpiperazin-2-one.NMR consistent with structure.

EXAMPLE 4 Synthesis of 2,2-dimethylpiperazine

A mixture of 3,3-dimethylpiperazin-2-one (8.28 kg, 64.6 mol) andtetrahydrofuran (THF) (60 kg) is heated to 50-60° C. giving a slightlyunclear solution. THF (50 kg) is stirred under nitrogen, and LiAlH₄ (250g, in a soluble plastic bag, from Chemetall) is added, which gives aslow evolution of gas. After gas evolution has ceased, more LiAlH₄ isadded (a total of 3.0 kg, 79.1 mol, is used), and the temperature risesfrom 22° C. to 50° C. because of an exoterm. The solution of3,3-dimethylpiperazin-2-one is added slowly over 2 hours at 41-59° C.The suspension is stirred for another hour at 59° C. (jacket temperature60° C.). The mixture is cooled, and water (3 l) is added over two hours,keeping the temperature below 25° C. (it is necessary to cool with ajacket temperature of 0° C.). Then sodium hydroxide (15%, 3.50 kg) isadded over 20 minutes at 23° C., cooling necessary. More water (9 l) isadded over half an hour (cooling necessary), and the mixture is stirredover night under nitrogen. Filter agent Celit (4 kg) is added, and themixture is filtered. The filter cake is washed with THF (40 kg). Thecombined filtrates are concentrated in the reactor until the temperaturein the reactor is 70° C. (distillation temperature 66° C.) at 800 mbar.The remanence (12.8 kg) is further concentrated on a rotavapor toapproximately 10 l. Finally, the mixture is fractionally distilled atatmospheric pressure, and the product is collected at 163-4° C. Yield5.3 kg (72%). NMR complies with the structure.

EXAMPLE 5 Synthesis oftrans-1-((1R,3S)-6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazinium(Compound I) Hydrogen Maleate Salt

Cis-(1S,3S)-3,5-dichloro-1-phenylindan (VI, LG=Cl) (240 g) is dissolvedin butan-2-one (1800 ml). Potassium carbonate (272 g) and 2,2-dimethylpiperazine (prepared in Example 4) (113 g) are added and the mixture isheated at reflux temperature for 40 h. To the reaction mixture is addeddiethyl ether (2 l) and hydrochloric acid (1M, 6 l). The phases areseparated, and pH in the water phase is lowered from 8 to 1 withconcentrated hydrochloric acid. The water phase is used to wash theorganic phase once again in order to ensure, that all product is in thewater phase. Sodium hydroxide (28%) is added to the water phase until pHis 10, and the water phase is extracted twice with diethyl ether (2 l).The diethyl ether extracts are combined, dried with sodium sulphate, andevaporated to dryness using a rotary evaporator. Yield 251 grams of thetitle compound as an oil. Cis/trans ratio, 82:18 according to NMR. Thecrude oil (ca. 20 grams) was further purified by flash chromatography onsilicagel (eluent: ethyl acetate/ethanol/triethylamine 90:5:5) followedby evaporation to dryness on a rotary evaporator. Yield 12 grams of thetitle compound as an oil (cis/trans ratio, 90:10 according to NM). Theoil is dissolved in ethanol (100 ml), and to this solution is added asolution of maleic acid in ethanol to pH 3. The resulting mixture isstirred at room temperature for 16 hours, and the formed precipitate iscollected by filtration. The volume of ethanol is reduced and anotherbatch of precipitate is collected. Yield 3.5 gram solid (no cis isomeris detected according to NMR) of the title compound. Enantiomeric excessis >99%. Melting point 175-178° C. NMR complies with the structure.

EXAMPLE 6 Synthesis of Compound I

A mixture oftrans-1-((1R,3S)-6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperaziniumhydrogen maleate (I) (9.9 grams), concentrated aqueous ammonia (100 ml),brine (150 ml) and ethyl acetate (250 ml) is stirred at room temperaturefor 30 min. The phases are separated, and the aqueous phase is extractedwith ethyl acetate once more. The combined organic phases are washedwith brine, dried over magnesium sulphate, filtered and evaporated todryness in vacuo. Yield 7.5 grams of oil. NMR complies with thestructure.

EXAMPLE 7 Synthesis oftrans-1-((1R,3S)-6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazinium(Compound I) Fumarate Salt

A solution oftrans-1-((1R,3S)-6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazine(obtained as described in example 6) (1 g) is dissolved in acetone (100mL). To this solution is added a solution of fumaric acid in ethanoluntil pH of the resulting solution is 4. The resulting mixture is cooledin an ice bath for 1.5 hours whereby a precipitate is formed. The solidcompound is collected by filtration. The compound was dried in vacuogiving a white solid compound (1.0 g). Enantiomeric excess is >99%.Melting point 193-196° C. NMR complies with the structure.

1. A compound having the name oftrans-1-((1R,3S)-6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazine anda formula of:

or a pharmaceutically acceptable salt thereof; wherein the compound isstereochemically pure.
 2. A pharmaceutical composition comprising thecompound of claim 1 and at least one pharmaceutically acceptablecarrier, filler or diluent.
 3. The pharmaceutical composition of claim2, wherein the compound is present in an enantiomeric excess of at least90%.
 4. A method of treating a subject suffering from a disease ordisorder comprising administering to the subject a therapeuticallyeffective amount of the compound of claim 1, wherein the disease ordisorder is selected from the group consisting of schizophrenia, ananxiety disorder, a depression, Schizophreniform Disorder,Schizoaffective Disorder, Delusional Disorder, Brief Psychotic Disorder,Shared Psychotic Disorder and mania in bipolar disorder.
 5. The methodof claim 4, wherein the disease or disorder is schizophrenia,Schizophreniform Disorder, Schizoaffective Disorder, DelusionalDisorder, Brief Psychotic Disorder, Shared Psychotic Disorder or maniain bipolar disorder.
 6. The method of claim 5, wherein the schizophreniacomprises positive symptoms.
 7. The method of claim 5, wherein theschizophrenia comprises negative symptoms.
 8. The method of claim 5,wherein the schizophrenia comprises depressive symptoms.
 9. The methodof claim 4, wherein the subject is treated with at least one othermedicament.
 10. A method of treating a subject suffering from a diseaseor disorder comprising administering to the subject a therapeuticallyeffective amount of the compound of claim 1, wherein: the disease ordisorder is selected from the group consisting of schizophrenia, ananxiety disorder, a depression, Schizophreniform Disorder,Schizoaffective Disorder, Delusional Disorder, Brief Psychotic Disorder,Shared Psychotic Disorder and mania in bipolar disorder; and thecompound is present in an enantiomeric excess of at least 90%.